Method and apparatus of delivery of inhaled nitric oxide to spontaneous-breathing and mechanically-ventilated patients

ABSTRACT

A device and method is disclosed for delivering NO to a patient. The device utilizes a single controller that controls two separate flow controllers to deliver an oxygen-containing gas and a NO-containing gas to the patient. The flow profiles of the oxygen-containing gas and the NO-containing gas are controlled by the controller. In one aspect of the invention, the flow profile of the NO-containing gas is proportional to the flow profile of the oxygen-containing gas throughout patient inspiration. In this regard, the patient receives a steady concentration of NO. In another aspect of the invention, the flow profile of the NO-containing gas is quasi-proportional to the flow profile of the oxygen-containing gas. In this regard, the NO-containing gas flow profile is altered to provide an increased concentration of NO either at the beginning or end of inspiration.

This application is a continuation of Ser. No. 09/449,240 filed Nov. 24,1999 and now U.S. Pat. No. 6,581,599, which is hereby incorporated byreference in its entirety.

The invention generally relates to an apparatus and method formeasurement, mixing, monitoring, and delivery of gases to a patient,including nitric oxide (“NO”) and oxygen. More specifically, theinvention relates to an apparatus and method of delivering gaseous NO tospontaneous-breathing patients as well as to patients connected to amechanical ventilator.

BACKGROUND OF THE INVENTION

NO is an environmental pollutant produced as a byproduct of combustion.At high concentrations (generally at or above 1000 ppm), NO is toxic. NOalso is a naturally occurring gas that is produced by the endotheliumtissue of the respiratory system. In the 1980's, it was discovered byresearchers that the endothelium tissue of the human body produced NO,and that NO is an endogenous vasodilator, namely, an agent that widensthe internal diameter of blood vessels.

With this discovery, numerous researchers have investigated the use oflow concentrations of inhaled NO to treat various pulmonary diseases inhuman patients. See Higenbottam et al., Am. Rev. Resp. Dis. Suppl.137:107, 1988. It was determined, for example, that PPH can be treatedby inhalation of low concentrations of NO. With respect to pulmonaryhypertension, inhaled NO has been found to decrease pulmonary arterypressure (PAP) as well as pulmonary vascular resistance (PVR).

Prior to the advent of NO inhalation therapy, pulmonary hypertension wastreated by the administration of drugs known as systemic vasodilators.These drugs, such as prostacyclin, nitroprusside, hydroalazine, andcalcium channel blockers suffered from the limitation that the drugs, bytheir nature, produced systemic effects. For example, the drugs not onlydecreased PAP levels, but also systemic blood pressure.

Unlike systemic vasodilators, inhaled NO acts as a selective pulmonaryvasodilator, acting primarily on the endothelium tissue of the lung.Upon inhalation, NO is absorbed into the capillary blood in theprecapillary airspaces and alveolar capillaries. Inhaled NO hasnegligible action beyond the site of its uptake since NO is rapidlyinactivated by the reaction with hemoglobin to form methemoglobin.

The use of inhaled NO for PPH patients was quickly followed by the useof inhaled NO for other respiratory diseases. For example, NO has beeninvestigated for the treatment of patients with increased airwayresistance as a result of emphysema, chronic bronchitis, asthma, adultrespiratory distress syndrome (ARDS), and chronic obstructive pulmonarydisease, (COPD). Still other respiratory diseases where NO inhalationtherapy is thought to be beneficial include, by way of illustration andnot by way of limitation: allograft lung transplantation,ischemia-reperfusion injury, congestive heart failure, septic shock, andhigh-altitude pulmonary edema.

While NO has shown promising preliminary results with respect to thetreatment and prevention of the diseases mentioned above, deliverymethods and devices must cope with certain problems inherent withgaseous NO delivery. First, exposure to high concentrations of NO istoxic. NO is toxic in high concentrations, especially over 1000 ppm.Even lower levels of NO can be harmful if the time exposure isrelatively high. For example, the Occupational Safety and HealthAdministration (OSHA) has set exposure limits for NO in the workplace at25 ppm time-weighted average for eight (8) hours. Typically, NO isadministrated to patients in the concentration range of about 1 ppm toabout 100 ppm.

Another problem with the delivery of NO is that NO rapidly oxidizes inthe presence of oxygen to form NO₂, which is highly toxic, even at lowlevels. For example, OSHA has set exposure limits for NO₂ at 5 ppm. Inany NO delivery device it is thus desirous to reduce, to the largestextent possible, the conversion of NO to NO₂. The rate of oxidation ofNO to NO₂ is dependent on numerous factors, including the concentrationof NO, the concentration of O₂, and the time available for reaction. Oneproblem with the inhalation of NO is that when NO is therapeuticallyinhaled, it is often mixed with high concentrations of O₂. Consequently,this increases the conversion rate of NO to NO₂. It is thus preferableto minimize the contact time between NO and O₂ when the NO is combinedwith a source of oxygen gas.

Methods and devices for delivering NO to a patient have been developedto minimize the conversion of NO to NO₂. For example, with respect tothe delivery of NO to patients connected to a mechanical ventilator, theNO/NO₂ stream has been introduced directly into the respiratory limb ofa patient. See Martin Francoe, et al., “Inhaled Nitric Oxide: TechnicalAspects of Administration and Monitoring,” Critical Care Medicine, Vol.26, No. 4, pp. 785-87 April 1998. This arrangement has the advantageover other designs that combine and mix NO/NO₂ and Air/O₂ prior to theirinput to the ventilator since the contact time between NO and O₂ isreduced.

Another delivery method and device that reduces the exposure to O₂ andto a certain extent NO is disclosed in the U.S. Pat. No. 5,839,433issued to Higenbottam. The '433 patent discloses a method and apparatusfor supplying NO to a patient. According to the '433 patent, a veryshort pulse of NO is delivered intermittently, either at the start orend of inspiration. The '433 patent thus teaches the delivery of a bolusor plug of nitric oxide to the patient by administering a very shortpulse of NO during inspiration. The timing of the delivery (beginningvs. late) is altered depending on the disease that is to be treated.When NO is desired in the lowermost depths of the lungs, for example,during treatment of pulmonary hypertension where NO acts on the smallpulmonary arteries and capillaries, a short pulse is given at thebeginning of inspiration. On the other hand, for asthma-like airwaydiseases, a very short pulse is administered near the end ofinspiration. This method attempts to deliver NO to the desired locationof the lungs. The method reduces the total exposure of the lungs to NOas well as reduces the total amount of NO available to react with O₂ toform toxic NO₂.

The pulses of NO delivered according to the '433 patent are of apredetermined width, which can be altered by changing the amount of timethat a control valve is left open. The '433 patent, however, fails todisclose the proportional delivery of NO gas to the patient having aflow profile that tracks or is proportional or quasi-proportional to theflow profile of an oxygen-containing gas. Rather, the valve mechanismprovides a bolus, or square wave-type “plug” of NO to the patient, thelength of which, is altered by adjusting its width (i.e., holding thevalve in the open position for a longer period of time). In this regard,the pulse has the flow profile of a square wave regardless of theprofile of the patient's inspiration profile.

Generally, NO is administered to patients that are either spontaneouslybreathing or connected to a mechanical ventilator. In spontaneouslybreathing patients, a patient typically wears a tight fitting mask,transtracheal O₂ catheter, nasal cannula, or other tubing passingdirectly into the airway of a patient. NO is typically mixed with O₂ andair prior to introduction into the patient airway. See Dean Hess, Ph.D.,et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory CareClinics of North America, Vol. 3, No. 3, pp. 402-404 Sep. 1997. Thesespontaneous systems, however, suffer from the limitation that the NOconcentration can fluctuate within a relatively wide range. The dose ofNO varies with the patient's ventilatory pattern due to the fact thatthe patient's inspiration profile changes on a breath-by-breath basis.The delivered dose of NO is thus approximated from assumptions regardingthe patient's ventilatory pattern.

There are several different methods of delivering NO to amechanically-ventilated patient. In one method, the NO/N₂ stream ispremixed with Air/O₂ prior to entering the ventilator. While suchpre-mixing may better permit the inspired concentration of NO to becontrolled, the production of NO₂ is significantly higher given thelonger contact time between NO and O₂. This is particularly true forventilators with large internal volumes.

In another method of delivery, NO is continuously injected into theinspiratory limb of the ventilator circuit. This method, however, hasdifficulty maintaining a stable NO concentration throughout the entireinspiration flow. Moreover, when continuously injected NO is used withadult ventilators that have phasic flow patterns (flow only duringinspiration), the inspiratory circuit fills with NO during expiration,and a large bolus of NO is delivered to the patient in the next breath.See, e.g. Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled NitricOxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, p. 381Sep. 1997. This method may result in an inspired NO concentration thatmay be more than double the calculated or estimated dose. In addition,the concentration of delivered NO varies with the length of thepatient's expiration. For example, when the expiratory time is short,the delivered NO concentration is lower due to less time for filling theinspiratory limb with NO.

Yet another method of delivering NO involves intermittent injections ofan NO-containing gas into the patient's inspiratory limb. In thisregard, NO is delivered into the inspiratory limb only during theinspiratory phase. For this method to be acceptable, however, the flowfrom the ventilator must be continuously and precisely measured, and theinjected does of NO must be precisely titrated such that the deliveredNO and inspiratory flow waveform are not affected. See, Dean Hess,Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” RespiratoryCare Clinics of North America, Vol. 3, No. 3, p. 384, Sep. 1997.

One such commercial device operating on the above-mentioned intermittentinjection principle is the I-NOvent Delivery System (Ohmeda). In theI-NOvent Delivery System a device separate and apart from the mechanicalventilator injects NO directly into the inspiration circuit of thepatient. Flow in the inspiration limb of the circuit is measured via aflow sensor and NO is injected in proportion to the measured flow toprovide the desired dose. See, Dean Hess, Ph.D., et al., “DeliverySystems for Inhaled Nitric Oxide,” Respiratory Care Clinics of NorthAmerica, Vol. 3, No. 3, p. 395, Sep. 1997.

Another commercial device utilizing intermittent injection of NO is theNOdomo device (Dragerwerk, Germany). The NOdomo device interfaces, likethe I-NOvent Delivery System, with a separate mechanical ventilator. NOaddition is controlled via a mass flow controller, adding a proportionof NO into the breathing circuit. Unlike the I-NOvent Delivery System,however, the NOdomo device controls NO flow delivery from an electronicflow controller that receives an input signal directly from theventilator. See, Dean Hess, Ph.D., et al., “Delivery Systems for InhaledNitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3,p. 399 Sep. 1997.

U.S. Pat. No. 5,558,083 issued to Bathe et al. discloses a NO deliverysystem. The delivery system can be used with a mechanical ventilator aswell as a gas proportioning device for spontaneous-breathing. A CPUcontrols a proportional control valve that is in-line with a source ofNO gas. The CPU calculates the desired flow from, among other things,the flow of breathing gas measured via a flow sensor 46 and NOconcentration measured by NO sensor 65. The proportional control valve24 is controlled is to arrive at the desired NO concentration.

In a second embodiment of the Bathe et al. device, a supplemental supplyof O₂ 74 is connected to the NO line. A proportional control valve 78 ispositioned in-line with the O₂ supply 74 and reports to the CPU 56. Asdisclosed in the '083 patent, the O₂ is provided as a safety measureshould the O₂ level fall below a critical level. Col. 8, lines 50-61. Inthe event that the level of O₂ has dropped below the minimum threshold,the CPU 56 directs the proportional flow controller to increase the flowof O₂ to the NO/N₂ stream.

The '083 patent, however, fails to teach or suggest theproportional-type control of NO/N₂, or O₂ to track or match the flow ofeither O₂ or the inspiration-profile of a patient. Rather, the O₂ isused as a safety measure should the O₂ concentration fall below athreshold value. Moreover, in the devices disclosed in the '083 and '433patents, residual NO gas is left in the device/inspiration limb betweenbreaths.

It is thus desirous to have a device and method of delivery of NO to apatient that can control the delivery of an NO-containing gas as well asan oxygen-containing gas to a patient via a single controller. Thedevice preferably can provide either a constant concentration of NO tothe patient during inspiration or a non-constant concentration of NO tothe patient depending on the desired setting. In addition, the devicepreferably does not suffer from the limitation of other deliverysystems, where NO may remain in the system between breaths. Namely, thedevice and method preferably eliminates any bolus or residue ofNO-containing gas that might build-up between breaths.

SUMMARY OF THE INVENTION

In a first aspect of the invention a method of delivering a steadyconcentration of NO to a spontaneously breathing, patient via deliverymeans is disclosed. The method includes the step of detecting the onsetof inspiration by the patient. The inspiration flow profile isdetermined for an individual breath. An oxygen-containing gas issupplied to the delivery means, wherein the oxygen-containing gas has aflow profile that tracks the inspiration flow profile. A NO-containinggas is supplied to the delivery means, wherein the NO-containing gas hasa flow profile that is proportionally less than the flow profile of theoxygen-containing gas throughout inspiration.

In a second, separate aspect of the invention, a method of delivering anon-constant concentration of nitric oxide to a spontaneously breathingpatient via delivery means is disclosed. The method includes the stepsof the first aspect, however, the NO-containing gas is supplied to thedelivery means wherein the NO-containing gas has a flow profile that isless than, but closely tracks the oxygen-containing gas flow profile atthe beginning of inspiration, and wherein the difference between theflow profile of the oxygen-containing gas and the flow profile of thenitric oxide-containing gas progressively increases through theremainder of inspiration.

In a third, separate aspect of the invention, another method ofdelivering a non-constant concentration of nitric oxide to aspontaneously breathing patient via delivery means is disclosed. Themethod includes the steps of the first aspect, however, the nitricoxide-containing gas has a flow profile that is substantially less thanthe oxygen-containing gas flow profile at the beginning of inspirationcompared to the end of inspiration, and wherein the difference betweenthe flow profile of the oxygen-containing gas and the flow profile ofthe nitric oxide-containing gas progressively decreases throughout theremainder of inspiration.

In another aspect of the invention, different embodiments of a deliverydevice, are disclosed for practicing the various methods for thedelivery of NO to a spontaneously breathing patient.

In yet another aspect of the invention, a method of delivering aconstant concentration of nitric oxide to a mechanically-ventilatedpatient via single controller is disclosed. In the method, the desiredinspiration flow profile is set in the controller. The flow rate of anoxygen-containing gas is varied in accordance with the inspiration flowprofile by delivering a first signal from said controller to a firstcontrol valve controlling the rate of flow of an oxygen-containing gasto the patient, thereby creating a flow profile of oxygen-containinggas. The flow rate of a nitric oxide-containing gas is varied inaccordance with the inspiration profile by delivering a second signalfrom said controller to a second control valve controlling the rate offlow of the nitric oxide-containing gas to the patient, creating a flowprofile of nitric oxide-containing gas. The nitric oxide-containing flowprofile is less than and proportional to the flow profile of theoxygen-containing gas throughout patient inspiration.

In still another aspect of the invention, a method of delivering anon-constant concentration of NO to a mechanically-ventilated patient isdisclosed. The method includes the steps of the previously recitedmethod, however, the flow rate of the nitric oxide-containing gas isvaried to create a flow profile of nitric oxide-containing gas that isless than, but closely tracks the oxygen-containing gas flow profile inthe beginning of the inspiration, wherein the difference between theflow profiles of the oxygen-containing gas and the nitricoxide-containing gas progressively increases through the remainder ofinspiration.

In yet another method for delivering a non-constant concentration of NOto a mechanically-ventilated patient, the flow rate of the nitricoxide-containing gas has a flow profile that is substantially less thanthe oxygen-containing gas flow profile at the beginning of inspiration,and wherein the difference between the flow profile of theoxygen-containing gas and the nitric oxide-containing gas progressivelydecreases throughout the remainder of inspiration.

In another aspect of the invention, different embodiments of a deliverydevice are disclosed for practicing the mechanical ventilation methodsset-forth above.

In another aspect of the invention, a method of delivering nitric oxidevia delivery means to a mechanically or spontaneously breathing patienthaving a certain inspiration profile is disclosed. The method includesthe aspect of an air flush to eliminate remaining nitric oxide orenriched oxygen. The method includes the step of supplying in a firstbreath a mixture of oxygen-containing gas and a nitric oxide-containinggas to the delivery means, the oxygen-containing gas and a nitricoxide-containing gas having a flow profile proportional or quasiproportional to the inspiration flow profile. In at least one nextbreath, a source of enriched oxygen-containing gas is supplied having aflow profile that is proportional or quasi-proportional to theinspiration flow profile. A source of air is supplied at or near the endof the first and next breaths to flush the delivery means of enrichedoxygen and nitric oxide.

In another aspect of the invention, a method of delivering nitric oxideto a spontaneously breathing patient via delivery means is disclosed.The method includes the step of detecting the onset of inspiration. Anoxygen-containing gas is supplied to the delivery means, wherein theoxygen-containing gas has a pre-programmed flow profile. A nitricoxide-containing gas is supplied to the delivery means, wherein thenitric oxide-containing gas has a pre-programmed flow profile that isproportional or quasi-proportional to the flow profile of theoxygen-containing gas throughout inspiration.

In still another aspect of the invention, a device for delivering nitricoxide to a spontaneous-breathing patient is disclosed. The deviceincludes a source of an oxygen-containing gas connected via tubing to apatient inspiration interface device. A source of a nitricoxide-containing gas is connected via tubing to the patient inspirationinterface device. A first proportional flow controller is locatedbetween the source of oxygen-containing gas and the patient inspirationinterface device for varying the flow rate of the oxygen-containing gasto the patient inspiration interface device. A second proportional flowcontroller is located between the source of nitric oxide-containing gasand the patient inspiration interface device for varying the flow rateof the nitric oxide-containing gas to the patient inspiration interfacedevice. An inspiration flow profile sensor is provided for detecting theonset of inspiration of the patient. The device includes a controllerfor controlling the first and second proportional flow controllers inresponse to the detection of the onset of inspiration from theinspiration flow profile sensor, the first and second proportional flowcontrollers being controlled such that the nitric oxide-containing gashas pre-programmed flow profile that is proportional orquasi-proportional to the flow profile of the oxygen-containing gasthroughout inspiration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of the device being used with apatient supported by mechanical ventilation.

FIG. 2(a) illustrates a square-shaped inspiration profile of theoxygen-containing gas and the NO-containing gas for delivering aconstant concentration of NO to a patient.

FIG. 2(b) illustrates a sine-shaped inspiration profile of theoxygen-containing gas and the NO-containing gas for delivering aconstant concentration of NO to a patient.

FIG. 2(c) illustrates a ramp-shaped inspiration profile of theoxygen-containing gas and the NO-containing gas for delivering aconstant concentration of NO to a patient.

FIG. 3(a) illustrates the inspiration profile of the oxygen-containinggas and the NO-containing gas for delivering a non-constantconcentration of NO to a patient, wherein the concentration of NO ishigher at the beginning of inspiration than at the end of inspiration.

FIG. 3(b) illustrates the inspiration profiles of the oxygen-containinggas and the NO-containing gas for delivering a non-constantconcentration of NO to a patient, wherein the concentration of NO ishigher at the end of inspiration than at the beginning of inspiration.

FIG. 4(a) is a flow profile of oxygen-containing gas and NO-containinggas where enriched-oxygen is delivered between breaths.

FIG. 4(b) shows the flow profile of the oxygen-containing gas, theNO-containing gas, and the air flush according to one aspect of theinvention.

FIG. 5 is a schematic illustration of a device being used with a patientsupported by mechanical ventilation wherein the air flush aspect isutilized.

FIG. 6 is a schematic illustration of the device being used with aspontaneously breathing patient.

FIG. 7(a) illustrates a inspiration profile for a spontaneouslybreathing patient in addition to the flow profiles of theoxygen-containing gas and the NO-containing gas for delivering aconstant concentration of NO to a patient.

FIG. 7(b) illustrates another inspiration profile for a spontaneouslybreathing patient in addition to the flow profiles of theoxygen-containing gas and the NO-containing gas for delivering aconstant concentration of NO to a patient.

FIG. 7(c) illustrates pre-programmed inspiration profiles of theoxygen-containing gas and the NO-containing gas.

FIG. 8(a) illustrates an inspiration profile for the oxygen-containinggas and the NO-containing gas for delivering a non-constantconcentration of NO to a patient, wherein the concentration of NO ishigher at the beginning of inspiration than at the end of inspiration.

FIG. 8(b) illustrates another inspiration profile for theoxygen-containing gas and the NO-containing gas for delivering anon-constant concentration of NO to a patient, wherein the concentrationof NO is higher at the end of inspiration than at the beginning of;inspiration.

FIG. 9(a) is a flow profile of oxygen-containing gas and NO-containinggas where enriched-oxygen is delivered between breaths.

FIG. 9(b) shows the flow profile of the oxygen-containing gas, theNO-containing gas, and the air flush according to one aspect of theinvention.

FIG. 10 is a schematic illustration of a device being used with aspontaneously-breathing patient wherein the air flush aspect isutilized.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring now to the Figures, FIG. 1 shows a schematic representation ofthe device 2 for delivering NO gas to a patient 4 connected to amechanical ventilator 6. In this embodiment of the invention, the device2 is the mechanical ventilator 6 since both control of patientinspiration, expiration, and delivery of NO are all controlled by thedevice 2. In this regard, a separate NO administration device is notneeded since the device 2/mechanical ventilator 6 delivers to NO gas tothe patient 4.

As seen in FIG. 1, the device 2 includes an inspiration limb 8 and anexpiration limb 10. The inspiration limb 8 and the expiration limb 10are connected via a Y-piece 12. The Y-piece 12 connects to deliverymeans for delivering the gaseous mixture to the patient 4. The deliverymeans preferably includes a patient inspiration interface device 14. Thepatient inspiration interface device 14 can be any number of devicesthat connect a generally hollow, tubular construction (i.e., flexibletubing) to the respiratory tract of the patient 4. For example, by wayof illustration and not by limitation, the patient inspiration interfacedevice 14 can include a tube for intubation into the patient's 4 airway,a nasal cannula, a face mask, or a transtracheal catheter. Flexible,hollow tubing is typically used in the inspiration limb 8 and expirationlimb 10. The expiration limb 10 returns to the device 2 where theexpired gases pass through an exhaust port 16. The expired gas can bevented to directly to the atmosphere, or alternatively, the expired gascan pass through an optional gas scavenger system 18 to remove NO andNO₂ from the expiration, gas prior to atmospheric venting.

The inspiration limb 8 is attached to the other end of the Y-piece 12and serves as a transport medium for the sources of oxygen-containinggas 20 and NO-containing gas 22 to the patient 4. The source ofoxygen-containing gas 20 can come from any number of sources, including,for example, atmospheric air, compressed air, compressed air enrichedwith oxygen, and a mixture of oxygen and N₂. The main requirement forthe oxygen-containing gas 20 is that the gas contain at least somecomponent of oxygen. Typically, when the device 2 is connected to apatient 4, the oxygen-containing gas 20 is delivered to the device via adedicated line in a medical facility having a pre-set oxygenconcentration. Alternatively, the oxygen-containing gas 20 can bedelivered via a pressurized cylinder.

The source of NO-containing gas 22 is shown in FIG. 1 as being apressurized cylinder 24 containing NO gas. While the use of apressurized cylinder 24 is the preferable method of storing theNO-containing gas 22, other storage and delivery means, such as adedicated feed line (wall supply), can also be used. Typically, theNO-containing gas 22 is a mixture of N₂ and NO. While N₂ is typicallyused to dilute the concentration of NO, any inert gas can also be used.When the NO-containing gas 22 is stored in pressurized cylinder 24, itis preferable that the concentration of NO in the pressurized cylinder24 fall within the range of about 800 ppm to about 1200 ppm. Commercialnitric oxide manufacturers typically produce nitric oxide mixtures formedical use at around the 1000 ppm range. Extremely high concentrationsof NO are undesirable because accidental leakage of NO gas is morehazardous, and high partial pressures of NO tends to cause thespontaneous degradation of NO into nitrogen.

While the inspiration concentration of NO gas generally falls within therange of about 1 ppm to about 100 ppm, it is preferable to use a sourceof NO-containing gas 22 at a higher concentration for several reasons.First, it is generally not possible to special-order or purchasepressurized cylinders 24 containing NO at a requested concentration.While it is possible to create pressurized cylinders 24 with lowerconcentrations of NO by mixing with an additional volume of inert gas,this process is time consuming, adds additional cost, and has thepotential of introducing oxygen into the gas mixture. U.S. Pat. No.5,839,433 issued to Higenbottam, for example, utilizes a lowconcentration source of NO. (100 ppm NO cylinder). Pressurized cylinders24 with low concentrations of NO are also not as desirable from aneconomic standpoint. Since a smaller quantity of NO is contained withinpressured cylinders 24 having low NO concentrations (i.e., 100 ppm),these pressurized cylinders 24 exhaust their supply of NO much morequickly than a pressurized cylinder 24 containing a higher concentrationof NO. Consequently, low NO ppm pressurized cylinders 24 are changedmore frequently than pressurized cylinders 24 having a largerconcentration of NO. This increases the overall cost of the NOtreatment.

Since the pressure in the pressurized cylinder 24 is relatively highcompared to the pressure of the breathing gas, a pressure regulator 26is preferably employed to reduce the pressure of the NO-containing gas22 prior to introduction to the ventilator 4.

The device 2 further includes a first control valve 30 that is locatedin-line between the oxygen-containing gas 20 and the inspiration limb 8.The first control valve 30 thus receives the oxygen-containing gas 20 atan input port and modulates, or controls the flow of theoxygen-containing gas 20 into the inspiration limb 8 through a secondexport port. The first control valve 30 can include, for example, aproportional control valve that opens (or closes) in a progressivelyincreasing (or decreasing if closing) manner depending on an electronicinput. As another example, the first control valve 30 can also include amass flow controller. The first control valve 30 can include any numberof control valves that can quickly and accurately alter the flow rate ofa gas across a relatively wide range of flow rates.

The output of the first control valve 30 leads to the inspiration limb 8of the patient 4. In this regard, the first control valve 30 controlsthe inspiration profile of the oxygen-containing gas 20. The inspirationprofile of the oxygen-containing gas 20 is the flow rate of theoxygen-containing gas 20 as a function of inspiration time. Theinspiration profile of the oxygen-containing gas 20 can be seen in FIG.2(a).

Still referring to FIG. 1, a second control valve 32 is located in-linebetween the NO-containing gas 22 and the inspiration limb 8. The secondcontrol valve 32 thus receives the NO-containing gas 22 at an input portand modulates, or controls the flow of the NO-containing gas 22 into theinspiration limb 8 through a second export port. The second controlvalve 32 can include, for example, a proportional control valve thatopens (or closes) in a progressively increasing (or decreasing ifclosing) manner depending on an electronic input. As another example,the second control valve 32 can also include a mass flow controller. Thesecond control valve 32 can include any number of control valves thatcan quickly and accurately alter the flow rate of a gas across arelatively wide range of flow rates. Like the first control valve 30,the inspiration profile of the second control valve 32 controls theinspiration profile of the NO-containing gas 22. The inspiration profileof the NO-containing gas 22 is the flow rate of the NO-containing gas 22as a function of time.

Exiting the second control valve 32 is a NO-addition line 34 that entersthe inspiration limb 8. The NO-addition line 34 thus carries thecontrolled flow of NO-containing gas 22 to the inspiration limb 8.Preferably, the NO-addition line 34 can enter the inspiration limb 8 atany point between the ventilator 6 and the patient inspiration interfacedevice 14. Most preferably, the NO-addition line 34 enters theinspiration limb 8 at a location that is prior to the Y-piece 12. Whenan optional gas monitor 44, described more fully below, is included aspart of the device 2 to measure the concentration of inspired gases inthe inspiration limb 8, the NO-addition line 34 preferably enters theinspiration limb 8 upstream of the location where the gas concentrationmeasurements are made. Even more preferably, the NO-addition line 34enters the inspiration limb 8 upstream of where the gas concentrationmeasurements are made at a distance that is equal to, or greater than,six-times the internal diameter of the tubing used in the inspirationlimb 8.

The device further includes CPU 36. The CPU 36 acts as a controller ofthe first and second control valves 30, 32. The CPU 36 sends, via signallines 38, 40, signals to control the opening and closing of the controlvalves 30, 32. As one option, the CPU 36 contains preset instructions oncontrolling the inspiration profiles of the oxygen-containing gas 20 andthe NO-containing gas 22. The instructions can be stored inread-only-memory (ROM) on the CPU 36, or alternatively, the instructionscan be input to the CPU 36 via an input device 42. The input device 42can be any number of devices that encode the flow profiles of theoxygen-containing gas 20 and the NO-containing gas 22. These include, byway of illustration, and not by way of limitation: a computer, adiskette, a control panel, and the like.

The input device 42 can input, for example, the set-point concentrationof NO in the breathing gas. The desired set-point concentration of NO istypically set by a physician, for example. The input device 42 can thusalter the degree of proportionality between the flow profile of theoxygen-containing gas 20 and the flow profile of the NO-containing gas22. A higher degree of proportionality (i.e., the flow profile of theNO-containing gas 22 more closely tracks the flow profile of theoxygen-containing gas 20) would generally produce a higher concentrationof inspired NO. The degree of proportionality also affects the timing ofthe NO gas purge.

The input device 42 may also input gas purge parameters to the CPU 36 todetermine when the flow profile of the NO-containing gas 22 istruncated. This can be done, for example, by establishing a time afterinspiration is started at which the flow profile of the NO-containinggas 22 is dropped to zero. Alternatively, the NO-containing gas 22 canterminate once the flow rate of the oxygen-containing gas 20 drops belowa certain pre-set level. These-settings can be input to the CPU 36 viathe input device 42.

By modulating the flow rates of both the oxygen-containing gas 20 andthe NO-containing gas 22, the CPU 36 controls the inspiration flowprofile of each breath of the patient. The CPU 36 can create any numberof inspiration-flow profiles. For example, the CPU 36 can deliver asine-shaped, square-shaped, or ramp-shaped inspiration flow profile. Ofcourse, other inspiration flow profiles other than those specificallymentioned-above can also be delivered to the patient 4. The CPU 36 canalso control other parameters such as the respiratory rate, tidalvolume, and inspiration pressure settings. These parameters can be sentto the CPU 36 via input device 42.

The present invention contemplates using a CPU 36 that gives the device2 complete programmability. In this regard, the flow profiles of theboth the oxygen-containing gas 20 and the NO-containing gas 22 can becontrolled during a single breath. While proportional andquasi-proportional flow profiles are disclosed in greater detail herein,it should be appreciated that any flow profile (of the oxygen-containinggas 20 or the NO-containing gas 22) can be produced for a single breathof a patient 4. Complete programmability is also possible where thedevice employs input device 42.

While CPU 36 is shown as the preferred controller for controlling theflow profiles of the oxygen-containing gas 20 and the NO-containing gas22, the present invention further contemplates using an analog switchingmechanism (not shown) as an alternative controller.

A description of the method of operation of the device 2 will now begiven. In the standard continuous mandatory ventilation mode, the device2 delivers to a patient 4 a preset tidal volume at a predeterminedrespiratory rate. The inspiration flow profile that is desired (e.g.,sine, square, or ramp) is delivered to the patient 4 by administering anoxygen-containing gas 20 and an NO-containing gas 22 that have flowprofiles that are similar to the inspiration flow profile that isdesired. FIGS. 2(a)-2(b) show the flow profiles of the oxygen-containingand NO-containing gases 20, 22. As can best be seen in FIG. 2(a), theflow profile of the NO-containing gas 22 is proportional to the flowprofile of the oxygen-containing gas 20. Proportional is meant toindicate that the flow rate of the NO-containing gas 22 is less than,but proportionally tracks the flow profile of the oxygen-containing gas20 throughout the patient's inspiration (the exception to this being theoptional truncation of NO flow as described more fully below). In thisregard, the delivered gas mixture of NO and oxygen has near constantconcentration. The patient 4 thus receives a steady concentration of NOthroughout inspiration.

The proportional flow is accomplished via the single CPU 36. The CPU 36sends signals to the first and second controller valves 30, 32 to keepthe flow of the NO-containing gas 22 lower, but in proportion to theflow of the oxygen-containing gas 20. Since a single CPU 36 is used tocontrol both the first and second control valves 30, 32, there is noneed to measure and report back to a control unit, the flow rate ofeither the NO-containing gas stream 22 or the oxygen-containing gasstream 20 via a flow sensor or the like.

The proportional flow control also has the benefit of purging theinspiration limb 8 of NO-containing gas 22 during certain inspirationflow patterns. For example, as seen in FIGS. 2(b) & 2(c), the flow rateof the NO-containing gas 22 reaches zero near the end portion ofinspiration while the oxygen-containing gas 20 continues to havepositive flow. In this regard, the flow of oxygen-containing gas 20purges the inspiration limb 8 of NO until the next breath.

Alternatively, the CPU 36 can send a close-valve signal to the secondcontrol valve 32 near the end of patient inspiration. This close-valvesignal truncates the flow profile (the truncated flow profile 52 isshown in FIGS. 2(a)-(c)) of the NO-containing gas 22 and leaves theoxygen-containing gas 20 as the only flow. The oxygen-containing gas 20thus purges the inspiration limb 8 of NO.

As an alternative embodiment, the CPU 36 controls the flow of theNO-containing gas 22 and the oxygen-containing gas 20 to provide for anon-constant concentration of NO in the breathing gas of a patient 4.FIGS. 3(a) & 3(b) show the flow profiles of the operation of the device2 according to this embodiment.

FIG. 3(a) shows a variable concentration delivery mode for NO thatprovides a higher concentration of NO to the patient 4 during thebeginning of inspiration. As seen in FIG. 3(a), the flow profile of theNO-containing gas 22 is less than the flow profile of theoxygen-containing gas 20. In addition, the flow profile of theNO-containing gas 22 closely tracks the oxygen-containing gas 20 flowprofile at the beginning of inspiration (quasi-proportional), but beginsto tail-off as inspiration progresses. In this manner, the differencebetween the flow profiles of the oxygen-containing gas 20 and theNO-containing gas 22 progressively increases through the remainder ofinspiration. In this method of delivery, a higher concentration of NO isdelivered to the patient 4 at the beginning of inspiration than at theend of inspiration. This flow profile is used when it is desirous for NOto be delivered deep within the lungs, for instance, to treat pulmonaryhypertension. Unlike the NO delivery method of the '433 patent thatdelivers a discrete bolus or short plug of NO, the present methodprovides a gradual gradient of NO in the lungs wherein the concentrationof NO in the upper airway is lower than the concentration of NO in thelowermost regions of the lung. In addition, the flow profile of theNO-containing gas 22 more closely matches the flow profile of theoxygen-containing gas 20. The flow profile of the NO-containing gas 22is not a square wave as disclosed in the '433 patent. Rather, the flowprofile is quasi-proportional to the oxygen-containing gas 20 profile.

This method is advantageous over the method of delivery disclosed in the'433 patent because the bolus delivered in the '433 patent is of such ashort length that the targeted area of the lung can be missed entirely.By having a continuous tapering of NO concentration, it is assured thatthe target area of the lungs is bathed in at least some concentration ofNO. Moreover, since the difference between the flow rate of theoxygen-containing gas 20 and the NO-containing gas 22 increases (ordecreases as shown in FIG. 3(b)) during the time of inspiration, thetotal amount of NO delivered per breath is smaller when compared to asquare wave profile of NO. The pressurized cylinder 24 containing theNO-containing gas 22 thus needs less frequent changing. Anotherimportant aspect of this method of delivery is that the flow profile ofthe NO-containing gas 22 reaches zero prior to the flow profile of theoxygen-containing gas 20. See FIGS. 3(a) and 3(b). The oxygen-containinggas 20 that continues to flow aids in purging the inspiration limb 8 ofNO.

With respect to the flow profile shown in FIG. 3(a), and as statedpreviously, the difference between the flow profiles of theoxygen-containing gas 20 and the NO-containing gas 22 progressivelyincreases through the remainder of inspiration. The rate of thisincrease, however, may be controlled by the CPU 36. For example, theincrease may be linear, non-linear, exponential, etc., depending on thedesired flow profile of the NO-containing gas 22. Further, the rate ofthis increase may be set by the input device 42.

Referring now to FIG. 3(b), another flow profile is shown for theNO-containing gas 22 that provides for a greater NO concentration at theend of the patient's 4 inspiration profile.

As seen in FIG. 3(b), the flow profile of the NO-containing gas 22 isless than the flow profile of the oxygen-containing gas 20. In addition,the flow profile of the NO-containing gas 22 is substantially less thanthe oxygen-containing gas 20 at the beginning of inspiration.Preferably, the flow rate of the NO-containing gas 22 is zero at thebeginning of inspiration, while the flow rate of the oxygen-containinggas 20 is positive. In addition, as inspiration proceeds, the differencebetween the flow profile of the oxygen-containing gas 20 and theNO-containing gas 22 progressively decreases. In this profile, a higherconcentration of NO is delivered to the upper airway region of thelungs. This method is used, for example, in breathing diseases relatingto broncho-constriction of the airways, such as asthma.

With respect to the flow profile shown in FIG. 3(b), the differencebetween the flow profiles of the oxygen-containing gas 20 and theNO-containing gas 22 progressively decreases through the remainder ofinspiration. The rate of this decrease, however, may be controlled bythe CPU 36. For example, the decrease may be linear, non-linear,exponential, etc., depending on the desired flow profile of theNO-containing gas 22. Further, the rate of this decrease may be set bythe input device 42.

With respect to the purge feature of this method, at the beginning ofthe inspiration profile, the oxygen-containing gas 20 is flowing, butthe NO-containing gas 22 is not. Consequently, the flow of theoxygen-containing gas 20 acts to purge the inspiration limb 8 of NO thatmay have remained from the previous breath.

In another flow profile, shown in FIG. 4(a), a patient 4 receives afirst inhalation containing both oxygen-containing gas 20 andNO-containing gas 22. In the next inhalation breath, the patientreceives just oxygen-containing gas 20. Preferably, this inspirationcontains a relatively high concentration of oxygen-containing gas 20(oxygen-enriched). In the third inspiration, the patient 4 againreceives an oxygen-containing gas 20 and an NO-containing gas 22. Whilethe flow profile shown in FIG. 4(a) is shown as alternating betweenoxygen-containing gas-only 20 and NO-containing gas 22 plusoxygen-containing gas 20, the profile could also include, for example,two or more oxygen-containing gas 22-only inspirations betweeninspirations having both oxygen-containing gas 20 and NO-containing gas22.

Yet another flow profile is shown in FIG. 4(b). In FIG. 4(b), a patient4 is delivered, on inspiration, a flow profile including anoxygen-containing gas 20 and a NO-containing gas 22. At or near the endof this inspiration, an air flush is delivered to the patient 4. The airflush serves to remove any NO-containing gas 22 that may be in theinspiration limb 8.

In the next inspiration, an oxygen-containing gas 20 is delivered to thepatient 4 without any NO-containing gas 22. Preferably, theoxygen-containing gas 20 includes an elevated level of oxygen(enriched-oxygen). At or near the end of this inhalation, another airflush is delivered to the patient 4. This air flush is delivered to thepatient 4 and serves to remove any enriched-oxygen remaining in theinspiration limb 8 as well as any residual NO gas.

In this embodiment, there are two separate sources of oxygen-containinggas 20. One source is the air used to flush the inspiration limb 8 whilethe other source is the enriched-oxygen-containing gas 20. The source ofair for the air flush can be, for example, a separate pressurizedcylinder, wall supply, compressor, pump, or the like. FIG. 5, forexample, shows the air being stored in a pressurized cylinder 25 whilethe enriched oxygen-containing gas 20 enters the device via a wallsupply or the like. The flow of air is modulated by a third controlvalve 33 that is controlled by the CPU 36 via signal line 41.

It should be noted that by controlling the flow rates of theoxygen-containing gas 20 and the NO-containing gas 22 via a single CPU36, the device 2 can use a pressurized cylinder 24 having a relativelyhigh concentration of NO (about 1000 ppm), since the, second flowcontroller 32 is always controlled to provide a smaller flow rate ofNO-containing gas 22 than the flow rate of the oxygen-containing gas 20.

The device 2 can further include an optional gas monitor 44. The gasmonitor 44 preferably monitors the concentration of one or more of thefollowing gases in the inspiration limb 8 of the device 2: oxygen, NO,and NO₂. The gas monitor 44 determines the concentration of gas(es) viaa sensor(s) 46 located in the inspiration limb 8. The sensor(s) 46 canbe a chemilluminesence-type, electrochemical cell-type, orspectrophotometric-type sensor 46 based on the accuracy and responsetime desired. The gas monitor 44 preferably includes a display screen 48that illustrates, on a real-time basis or as close to a real-time basisas possible, the concentrations of the measured gases. The gas monitor44 preferably reports the gas concentration data to the CPU 36 viasignal line 50.

As an optional safety feature of the device 2, the CPU 36 can use thereal-time concentration data to determine if the NO or NO₂ concentrationlevels exceed certain predetermined set-points input via input device42. For example, if the NO₂ concentration exceeds the set-pointconcentration, the CPU can send a close-valve signal to the second.control valve 32. In this regard, the NO-containing gas 22 is shut-offentirely.

In addition, the level of oxygen in the gas stream can also be monitoredvia the monitor 44. If the oxygen concentration drops below a certainconcentration, the CPU 36 can decrease the flow of the NO-containing gas22 and/or increase the flow rate of the oxygen-containing gas 20.

It should be noted that the above-described device 2 can also be used inmodes other than continuous mandatory ventilation. For example, thedevice 2 can also-be used with assisted ventilation, synchronizedintermittent ventilation (SIMV), intermittent mandatory ventilation(IMV), and pressure support ventilation. Still other modes of operationwill also work with the device 2.

In another separate aspect of the invention, as shown in FIG. 6, adevice 60 for a spontaneously breathing patient 4 is disclosed. Thedevice 60 includes an oxygen-containing gas limb 62 and a NO-containinggas limb 64. Both the oxygen-containing gas limb 62 and a NO-containinggas limb 64 are preferably made of a hollow, flexible tubing material.The oxygen and NO limbs 62, 64 combine at a mixing point 66. The mixingpoint 66 may include a Y-piece 68 that connects with another hollowflexible tube that then travels to the patient 4. The combined gasesenter the patient's airway via delivery means. The delivery meanspreferably includes a patient inspiration interface device 70. By way ofillustration and not by way of limitation, the patient inspirationinterface device 70 can include a tube for intubation into the patient's4 airway, a nasal cannula, a face mask, or transtracheal catheter.

A source 72 of oxygen-containing gas 20 delivers the oxygen-containinggas 20 into the oxygen-containing gas limb 62. The source 72 ofoxygen-containing gas 20 preferably is a pressurized cylinder 74. Thepressurized cylinder 74 can contain atmospheric air, compressed air,compressed air mixed with oxygen, or a mixture of oxygen and nitrogen.The main requirement for the oxygen source 72 is that the gas contain atleast some component of oxygen.

While the pressurized cylinder 74 is the preferable method of storingthe oxygen source 72, other storage means such as a dedicated feed line(wall supply), can also be used. Alternatively, the oxygen can bedelivered from a compressor or pump.

The NO source 76 is shown as a pressurized cylinder 74. While the use ofa pressurized cylinder 74 is the preferable method of storing theNO-containing gas 22, other storage and delivery means, such as adedicated feed line, can also be used. Preferably, the NO-containing gas22 is a mixture of N₂ and NO. While N₂ is typically used to dilute theconcentration of NO, any inert gas can also be used. When theNO-containing gas 22 is stored in pressurized cylinder 74, it ispreferable that the concentration of NO in the cylinder fall within therange of about 800 ppm to about 1200 ppm.

As with the inspiration concentration of NO gas in the mechanicalventilator embodiment, it is generally preferable that the NOconcentration fall with the range of about 1 ppm to about 100 ppm. Inthe spontaneous-breathing embodiment, it is preferable to use a NOsource 76 at higher concentrations for the same stated reasons for themechanical ventilator embodiment.

When pressurized cylinders 74 are used to store the oxygen andNO-containing gases 20, 22, pressure regulators 78 are preferably usedto reduce the pressures of the respective gases.

The device 60 includes a first control valve 80 that is located in-linebetween the source 72 of oxygen-containing gas 20 and theoxygen-containing gas limb 62. As with the mechanical ventilator device2. The first control valve 80 thus receives the oxygen-containing gas 20at an input port and modulates, or controls the flow of theoxygen-containing gas 20 into the oxygen-containing gas limb 62 througha second export port. The first control valve 80 can include, forexample, a proportional control valve that opens (or closes) in aprogressively increasing (or decreasing if closing) manner depending onan electronic input. As another example, the first control valve 80 canalso include a mass flow controller. The first control valve 80 caninclude any number of control valves that can quickly and accuratelyalter the flow rate of a gas across a relatively wide range of flowrates.

The output of the first control valve 80 leads to the oxygen-containinggas limb 62 of the patient 4. In this regard, the first control valve 80controls the inspiration profile of the oxygen-containing gas 20. Theinspiration profile of the oxygen-containing gas 20 is the flow rate ofthe oxygen-containing gas 20 as a function of inspiration time. Theinspiration profile of the oxygen-containing gas 20 can be seen in FIGS.7(a) and 7(b).

Still referring to FIG. 6, a second control valve 82 is located in-linebetween the NO-containing gas 22 and the NO-containing gas limb 64. Thesecond control valve 82 thus receives the NO-containing gas 22 at aninput port and modulates, or controls the flow of the NO-containing gas22 into the NO-containing gas limb 64 through a second export port. Thesecond control valve 82 can include, for example, a proportional controlvalve that opens (or closes) in a progressively increasing (ordecreasing if closing) manner depending on an electronic input. Asanother example, the second control valve 82 can also include a massflow controller. The second control valve 82 can include any number ofcontrol valves that can quickly and accurately alter the flow rate of agas across a relatively wide range of flow rates. Like the first controlvalve 80, the inspiration profile of the second control valve 82controls the inspiration profile of the NO-containing gas 22. Theinspiration profile of the NO-containing gas 22 is the flow rate of theNO-containing gas 22 as a function of time.

The spontaneously breathing device 60 includes a CPU 84. The CPU 84controls the first and second control valves 80, 82. The CPU 84 sends,via signal lines 86, 88, signals to control the opening and closing ofthe control valves 80, 82.

The device 60 further includes an inspiration flow profile sensor 90that is positioned in the patient 4 breathing limb. Preferably, theinspiration flow profile sensor 90 is located downstream of the mixingpoint 66, but upstream of the patient inspiration interface device 70.In one aspect, the inspiration flow profile sensor 90 detects the flowrate of the inspired gas by the patient 4. The inspiration flow profilesensor 90 thus detects the onset of inspiration as well as theinspiration flow profile throughout the remainder of the breath. Theflow profile sensor 90 can include any number of devices, includingventuri-based sensor, hot wire anemometer, rotating vane, thermal flow,pressure transducer, and the like. Preferably, a flow profile sensor 90is used that can rapidly detect small changes in the breathing flow rateover a wide range of flow rates.

In another aspect, the flow profile sensor 90 detects only the onset ofinspiration by the patient 4.

The inspiration profile sensor 90 reports the inspiration flow rate databack to the CPU 84 via signal line 92 on preferably a real-time basis(or as close to a real-time basis as possible). The flow rate datareported back to the CPU 84 is the flow rate of the breathing gas(oxygen-containing gas 20 and NO-containing gas 22) as a function oftime. This data represents the inspiration flow profile for eachindividual breath.

As an alternative to measuring the flow rate of the breathing gas as afunction of time, the inspiration profile sensor 90 can just measure theonset of inspiration. The data reflecting the onset of inspiration isdelivered as a signal to CPU 84. Pre-programmed flow profiles of theoxygen-containing gas 20 and the NO-containing gas 22 are then deliveredto the patient 4. In general, the pre-programmed flow profiles of theoxygen-containing gas 20 and the NO-containing gas 22 are determined byempirical studies of patient inhalation characteristics. The flowprofile of the oxygen-containing gas 20 and the NO-containing gas 22 canbe proportional, quasi-proportional, or any other pre-determined flowpattern. This aspect is shown, for example, in FIG. 7(c).

Based on the signal received from the inspiration profile sensor 90, theCPU 84 controls both the first and second control valves 80, 82 todelivery respective flow profiles of oxygen and NO. In one aspect of theinvention, the CPU 84 contains instructions to deliver proportionalflows of both the oxygen-containing gas 20 and the NO-containing gas 22.In this regard, a steady concentration of NO is delivered to thepatient. This flow pattern is embodied in FIGS. 7(a) & 7(b). Thedotted-line in FIG. 1 illustrates the inspiration flow profile of thepatient 4. As can be seen in FIGS. 7(a) & 7(b), not only is the flow ofthe oxygen-containing gas 20 proportional to the inspirational flow ofthe patient 4, the flow of the NO-containing gas 22 is proportional toboth the inspirational flow of the patient 4 as well as theinspirational flow of the oxygen-containing gas 20.

The device 60 preferably includes an input device 94. The input device94 can be any number of devices including, for example, a computer,diskette, control panel, and the like. The input device 94 can control,for example, the set-point concentration of NO in the breathing gas. Theinput device 94 can thus alter the degree of proportionality between theflow profile of the oxygen-containing gas 20 and the flow profile of theNO-containing gas 22. A higher degree of proportionality (i.e., the flowprofile of the NO-containing gas 22 more closely tracks the flow profileof the oxygen-containing gas 20) would generally produce a higherconcentration of inspired NO. The degree of proportionality also affectsthe timing of the NO gas purge.

The input device 94 may also input gas purge parameters to the CPU 84 todetermine when the flow profile of the NO-containing gas 22 istruncated. This can be done, for example, by establishing a time afterinspiration is started at which the flow profile of the NO-containinggas 22 is dropped to zero. Alternatively, the NO-containing gas 22 d canterminate once the flow rate of the oxygen-containing gas 20 drops belowa certain pre-set level. These settings can be input to the CPU 84 viathe input device 94.

Still referring to FIGS. 7(a) & 7(b), the proportional flow of theNO-containing gas 22 also provides the device 60 and method with a purgefeature to purge any NO gas from the lines and the patient inspirationinterface device 70. At both the beginning and end of the patient's 4inspiration, there is a positive flow of the oxygen-containing gas 20,while the flow of the NO-containing gas 22 is zero. Consequently, at thebeginning and end of each breath, the device is purged on NO gas.

With respect to the spontaneous-breathing embodiment, the presentinvention also contemplates using a CPU 84 that gives the device 60complete programmability. In this regard, the flow profiles of the boththe oxygen-containing gas 20 and the NO-containing gas 22 can becontrolled during a single breath. While proportional andquasi-proportional flow profiles are disclosed in greater detail herein,it should be appreciated that any flow profile (of the oxygen-containinggas 20 or the NO-containing gas 22) can be produced for a single breathof a patient 4. Complete programmability is also possible where thedevice employs input device 94.

While CPU 84 is shown as the preferred controller for controlling theflow profiles of the oxygen-containing gas 20 and the NO-containing gas22, the present invention further contemplates using an analog switchingmechanism (not shown) as an alternative controller.

The device 60 can further include an optional gas monitor 96. The gasmonitor 96 preferably monitors the concentration of one or more of thefollowing gases in the inspiration limb of the device 60: oxygen, NO,and NO₂. The gas monitor 96 determines the concentration of gas(es) viaa sensor(s) 98 located in the inspiration limb. The sensor(s) 98 can bea chemilluminesence-type, electrochemical cell-type, orspectrophotometric-type sensor 98 based on the accuracy and responsetime desired. The gas monitor 96 preferably includes a display screen100 that illustrates, on a real-time basis or as close to a real-timebasis as possible, the concentrations of the measured gases.

Referring now to FIG. 8(a), a separate aspect of thespontaneous-breathing device 60 will now be disclosed. In this aspect ofthe invention, a non-constant concentration of NO is delivered to thepatient 4. In one aspect, the flow profile of the NO-containing gas 22is such that a higher concentration of NO is delivered at the beginningof inspiration than the concentration delivered near the end ofinspiration. In this aspect, the flow profile of the NO-containing gas22 is less than flow profile of the oxygen-containing gas 20 and closelytracks the oxygen-containing gas 20 flow profile at the beginning ofinspiration (quasi-proportional), but begins to tail-off as inspirationprogresses. In this manner, the difference between the flow profiles ofthe oxygen-containing gas 20 and the NO-containing gas 22 progressivelyincreases through the remainder of inspiration. This flow profile isused when it is desirous for NO to be delivered deep within the lungs,for instance, to treat pulmonary hypertension. This method of delivery,as stated previously, provides a gradual gradient of NO through the inthe lungs rather than a bolus of NO that is disclosed in the '433patent.

With respect to the flow profile shown in FIG. 8(a), and as statedpreviously, the difference between the flow profiles of theoxygen-containing gas 20 and the NO-containing gas 22 progressivelyincreases through the remainder of inspiration. The rate of thisincrease, however, may be controlled by the CPU 84. For example, theincrease may be linear, non-linear, exponential, etc., depending on thedesired flow profile of the NO-containing gas 22. Further, the rate ofthis increase may be set by the input device 94.

This delivery method also contains gas purge feature that purges any NOgas from the lines and the patient inspiration interface device 70. Atthe end of the patient's 4 inspiration, there is a positive flow of theoxygen-containing gas 20, while the flow of the NO-containing gas 22 iszero. At this point in the patient's inspiration, the flow ofoxygen-containing gas 20 purges the system of NO gas.

Referring now to FIG. 8(b), another flow profile is shown for theNO-containing gas 22 that provides for a greater NO concentration at theend portion of a patient's 4 inspiration. In this flow profile, the flowprofile of the NO-containing gas 22 is substantially less than theoxygen-containing gas 20 flow profile. Most preferably, the flow profileof the NO-containing gas 22 starts out at zero, while the flow profileof the oxygen-containing gas 20 is positive. The flow profile of theNO-containing gas 22 begins to more closely track the flow profile ofthe oxygen-containing gas 20, wherein the difference between the flowprofile of the oxygen-containing gas 20 and the NO-containing gas 22progressively decreases throughout the remainder of inspiration. In thisflow profile, a higher concentration of NO is delivered to the upperairway region of the lungs. This method is used, as stated previously,in breathing diseases relating to broncho-construction of the airways,such as asthma.

With respect to the flow profile shown in FIG. 8(b), the differencebetween the flow profiles of the oxygen-containing gas 20 and theNO-containing gas 22 progressively decreases through the remainder ofinspiration. The rate of this decrease, however, may be controlled bythe CPU 84. For example, the decrease may be linear, non-linear,exponential, etc., depending on the desired flow profile of theNO-containing gas 22. Further, the rate of this decrease may be set bythe input device 94.

This delivery method also contains gas purge feature that purges any NOgas from the lines and the patient inspiration interface device 70. Atthe beginning of the patient's 4 inspiration, there is a positive flowof the oxygen-containing gas 20, while the flow of the NO-containing gas22 is zero. At this point in the patient's inspiration, the flow ofoxygen-containing gas 20 purges the system of NO gas. Consequently, anyremaining NO that might have remained in the lines and/or patientinspiration interface device 70 from the previous breath are purged bythe flow of the oxygen-containing gas 20.

In another flow profile, shown in FIG. 9(a), a patient 4 receives afirst inhalation containing both oxygen-containing gas 20 andNO-containing gas 22. In the next inhalation breath, the patientreceives just oxygen-containing gas 20. Preferably, this inspirationcontains a relatively high concentration of oxygen-containing gas 20(oxygen-enriched). In the third inspiration, the patient 4 againreceives an oxygen-containing gas 20 and an NO-containing gas 22. Whilethe flow profile shown in FIG. 9(a) is show as alternating betweenoxygen-containing gas-only 20 and NO-containing gas 22 plusoxygen-containing gas 20, the profile could also include, for example,two or more oxygen-containing gas 22-only inspirations betweeninspirations having both oxygen-containing gas 20 and NO-containing gas22.

Yet another flow profile is shown in FIG. 9(b). In FIG. 9(b), a patient4 is delivered, on inspiration, a flow profile including anoxygen-containing gas 20 and a NO-containing gas 22. At or near the endof this inspiration, an air flush is delivered to the patient 4. The airflush serves to remove any NO-containing gas 22 that may be in theinspiration limb 8.

In the next inspiration, an oxygen-containing gas 20 is delivered to thepatient 4 without any NO-containing gas 22. Preferably, theoxygen-containing gas 20 includes an elevated level of oxygen(enriched-oxygen). At or near the end of this inhalation, another airflush is delivered to the patient 4. This air flush is delivered to thepatient 4 and serves to remove any enriched-oxygen gas remaining in theinspiration limb 8.

In this embodiment, there are two separate sources of oxygen-containinggas 20. One source is the air used to flush the device 60 while theother source is the enriched-oxygen-containing gas 20. The source of airfor the air flush can be, for example, a separate pressurized cylinder,wall supply, compressor, pump, or the like. FIG. 10, for example, showsthe air being stored in a pressurized cylinder 75 while the enrichedoxygen-containing gas 20 enters the device via a wall supply or thelike. The flow of air is modulated by a third control valve 83 that iscontrolled by the CPU 84 via signal line 89.

While embodiments of the present invention have been shown anddescribed, various modifications may be made without departing from thescope of the present invention, and all such modifications andequivalents are intended to be covered.

What is claimed is:
 1. A method of delivering a steady concentration ofnitric oxide to a spontaneously breathing patient via delivery meanscomprising the steps of: detecting the onset of inspiration; determiningthe inspiration flow profile for an individual breath; supplying anoxygen-containing gas to the delivery means, the oxygen-containing gashaving a flow profile that tracks the inspiration flow profile; andsupplying an nitric oxide-containing gas to the delivery means, thenitric oxide-containing gas having a flow profile that is proportionallyless than the flow profile of the oxygen-containing gas throughoutinspiration.
 2. A method according to claim 1, wherein the methodfurther includes the step of monitoring the concentration of one or moreof the following gases prior to the delivery means: oxygen, nitricoxide, and nitrogen dioxide.
 3. A method according to claim 1, whereinthe flow profile of the nitric oxide-containing gas reaches zero flow ata time near the end of the patient inspiration flow profile, and whereinwhen said flow reaches zero, the flow profile of the oxygen-containinggas is greater than zero such that the oxygen-containing gas purges theinspiration limb of nitric oxide-containing gas.
 4. A method accordingto claim 1, wherein the flow profile of the nitric oxide-containing gasis zero flow at the beginning of the patient inspiration flow profile,and wherein when said flow is zero, the flow profile of theoxygen-containing gas is greater than zero such that theoxygen-containing gas purges the inspiration limb of nitricoxide-containing gas.
 5. A method according to claim 1, wherein the flowprofile of the nitric oxide-containing gas is zero at the beginning ofthe patient inspiration profile while the flow profile of theoxygen-containing gas is greater than zero, and wherein at a time nearthe end of the patient inspiration flow profile, the flow profile of thenitric oxide-containing gas is zero while the flow profile of theoxygen-containing gas is greater than zero, wherein when the nitricoxide-containing gas flow reaches zero and the flow profile of theoxygen-containing gas is greater than zero the oxygen-containing gaspurges the inspiration limb of nitric oxide-containing gas.
 6. A methodaccording to claim 1, further comprising the step of truncating the flowprofile of the nitric oxide-containing gas to zero near the end ofpatient inspiration.
 7. A method according to claim 1, wherein thedelivery means is a nasal cannula.
 8. A method according to claim 1,wherein the delivery means is a face mask.
 9. A method according toclaim 1, wherein the delivery means is a transtracheal catheter.
 10. Amethod according to claim 1, wherein the delivery means is anendotracheal tube.
 11. A device for delivering nitric oxide to aspontaneous-breathing patient comprising: a source of anoxygen-containing gas connected via tubing to a patient inspirationinterface device; a source of an nitric oxide-containing gas connectedvia tubing to the patient inspiration interface device; a firstproportional flow controller located between the source ofoxygen-containing gas and the patient inspiration interface device forvarying the flow rate of the oxygen-containing gas to the patientinspiration interface device; a second proportional flow controllerlocated between the source of nitric oxide-containing gas and thepatient inspiration interface device for varying the flow rate of thenitric oxide-containing gas to the patient inspiration interface device;an inspiration flow profile sensor that measures the inspiration flowprofile of the inspiration breath of the patient; and a controller forcontrolling the first and second proportional flow controllers inresponse to the inspiration flow profile from the inspiration flowprofile sensor, the first and second proportional flow controllers beingcontrolled such that the oxygen-containing gas has a flow profile thattracks the inspiration flow profile, and wherein the nitricoxide-containing gas has a flow profile that is proportionally less thanthe oxygen-containing gas throughout inspiration.
 12. A device accordingto claim 11, the controller controlling the second proportional flowcontroller to stop the flow of the nitric oxide-containing gas at a timenear the end of inspiration, and wherein the oxygen-containing gascontinues to flow to purge the tubing and the patient inspirationinterface device of nitric oxide.
 13. A device according to claim 12,the device further including an input device to input gas purgeparameters to the controller to truncate the flow profile of the nitricoxide-containing gas.
 14. A device according to claim 11, the devicefurther including at least one sensor located prior to the patientinspiration interface device for measuring the concentration of one ormore of the following gases: oxygen, nitric oxide, and nitrogen dioxide.15. A device according to claim 11, wherein the patient inspirationinterface device is a face mask.
 16. A device according to claim 11,wherein the patient inspiration interface device is a nasal cannula. 17.A device according to claim 11, wherein the patient inspirationinterface device is a transtracheal catheter.
 18. A device according toclaim 11, further including an input device that inputs aproportionality set-point to control the degree of proportionalitybetween the oxygen-containing gas and the nitric oxide-containing gas.19. The device according to claim 11, wherein the source of theoxygen-containing gas is a pressurized cylinder.
 20. The deviceaccording to claim 11, wherein the source of the oxygen-containing gasis a wall gas supply.
 21. The device according to claim 11, wherein thesource of the oxygen-containing gas is an air compressor.
 22. A methodof delivering a non-constant concentration of nitric oxide to amechanically-ventilated patient via single controller, the mechanicalventilator having an inspiration limb and an expiration limb, the methodcomprising the steps of: setting the desired inspiration flow profile inthe controller; varying the flow rate of an oxygen-containing gas inaccordance with the inspiration flow profile by delivering a firstsignal from said controller to a first control valve controlling therate of flow of an oxygen-containing gas to the patient, therebycreating a flow profile of oxygen-containing gas; varying the flow rateof a nitric oxide-containing gas in accordance with the inspirationprofile by delivering a second signal from said controller to a secondcontrol valve controlling the rate of flow of the nitricoxide-containing gas to the patient, creating a flow profile of nitricoxide-containing gas that is less than, but closely tracks theoxygen-containing gas flow profile in the beginning of the inspiration,wherein the difference between the flow profiles of theoxygen-containing gas and the nitric oxide-containing gas progressivelyincreases through the remainder of inspiration; and monitoring theconcentration of one or more of the following gases in the inspirationlimb oxygen, nitric oxide, and nitrogen dioxide.
 23. A device fordelivering nitric oxide to a patient that is mechanically-ventilatedcomprising; a source of an oxygen-containing gas connected to a patientinspiration limb; a source of a nitric oxide-containing gas connected tothe patient inspiration limb; a first proportional flow control valvelocated between the source of oxygen-containing gas and the patient forvarying the flow rate of the oxygen-containing gas to the patient; asecond proportional flow controller located between the source of nitricoxide-containing gas and the patient for varying the flow rate of thenitric oxide-containing gas to the patient; a controller includinginstructions for the inspiration flow profile, the controller furthercontrolling the first and second proportional flow controllers inresponse to the inspiration flow profile, the first and secondproportional flow controllers being controlled such that theoxygen-containing gas has a flow profile that tracks the inspirationflow profile, and wherein the nitric oxide-containing gas has a flowprofile that is proportionally less than the oxygen-containing gasthroughout inspiration.
 24. A device according to claim 22, thecontroller containing instructions for truncating the flow profile ofthe nitric oxide-containing gas to zero near the end of patientinspiration.
 25. A device for delivering nitric oxide to a patient thatis mechanically-ventilated comprising; a source of an oxygen-containinggas connected to a patient inspiration limb; a source of a nitricoxide-containing gas connected to the patient inspiration limb; a firstproportional flow control valve located between the source ofoxygen-containing gas and the patient for varying the flow rate of theoxygen-containing gas to the patient; a second proportional flowcontroller located between the source of nitric oxide-containing gas andthe patient for varying the flow rate of the nitric oxide-containing gasto the patient; a controller including instructions for the inspirationflow profile, the controller further controlling the first and secondproportional flow controllers in response to the inspiration flowprofile, the first and second proportional flow controllers beingcontrolled such that the oxygen-containing gas has a flow profile thattracks the inspiration flow profile, and wherein the nitricoxide-containing gas flow profile is less than, but closely tracks theoxygen-containing gas flow profile in the beginning of the inspiration,wherein the difference between the flow profiles of theoxygen-containing gas and the nitric oxide-containing gas progressivelyincreases through the remainder of inspiration.
 26. A device fordelivering nitric oxide to a patient that is mechanically-ventilatedcomprising; a source of an oxygen-containing gas connected to a patientinspiration limb; a source of a nitric oxide-containing gas connected tothe patient inspiration limb; a first proportional flow control valvelocated between the source of oxygen-containing gas and the patient forvarying the flow rate of the oxygen-containing gas to the patient; asecond proportional flow controller located between the source of nitricoxide-containing gas and the patient for varying the flow rate of thenitric oxide-containing gas to the patient; a controller includinginstructions for the inspiration flow profile, the controller furthercontrolling the first and second proportional flow controllersin-response to the inspiration flow profile, the first and secondproportional flow controllers being controlled such that theoxygen-containing gas has a flow profile that tracks the inspirationflow profile, and wherein the nitric oxide-containing gas flow profilehaving a flow profile that is substantially less than theoxygen-containing gas flow profile at the beginning of inspiration, andwherein the difference between the flow profile of the oxygen-containinggas and the nitric oxide-containing gas progressively decreasesthroughout the remainder of inspiration.
 27. A device for deliveringnitric oxide to a spontaneous-breathing patient comprising: a source ofan oxygen-containing gas connected via tubing to a patient inspirationinterface device; a source of an nitric oxide-containing gas connectedvia tubing to the patient inspiration interface device; a firstproportional flow controller located between the source ofoxygen-containing gas and the patient inspiration interface device forvarying the flow rate of the oxygen-containing gas to the patientinspiration interface device; a second proportional flow controllerlocated between the source of nitric oxide-containing gas and thepatient inspiration interface device for varying the flow rate of thenitric oxide-containing gas to the patient inspiration interface device;an inspiration flow profile sensor that measures the inspiration flowprofile of the inspiration breath of the patient; and a controller forcontrolling the first and second proportional flow controllers inresponse to the inspiration flow profile from the inspiration flowprofile sensor, the first and second proportional flow controllers beingcontrolled such that the oxygen-containing gas has a flow profile thattracks the inspiration flow profile, and wherein the nitricoxide-containing gas flow profile having a flow profile that issubstantially less than the oxygen-containing gas flow profile at thebeginning of inspiration, and wherein the difference between the flowprofile of the oxygen-containing gas and the nitric oxide-containing gasprogressively decreases throughout the remainder of inspiration.
 28. Adevice for delivering nitric oxide to a spontaneous-breathing patientcomprising: a source of an oxygen-containing gas connected via tubing toa patient inspiration interface device; a source of an nitricoxide-containing gas connected via tubing to the patient inspirationinterface device; a first proportional flow controller located betweenthe source of oxygen-containing gas and the patient inspirationinterface device for varying the flow rate of the oxygen-containing gasto the patient inspiration interface device; a second proportional flowcontroller located between the source of nitric oxide-containing gas andthe patient inspiration interface device for varying the flow rate ofthe nitric oxide-containing gas to the patient inspiration interfacedevice; an inspiration flow profile sensor that measures the inspirationflow profile of the inspiration breath of the patient; and a controllerfor controlling the first and second proportional flow controllers inresponse to the inspiration flow profile from the inspiration flowprofile sensor, the first and second proportional flow controllers beingcontrolled such that the oxygen-containing gas has a flow profile thattracks the inspiration flow profile, and wherein the nitricoxide-containing gas flow profile having a flow profile that issubstantially less than the oxygen-containing gas flow profile at thebeginning of inspiration, and wherein the difference between the flowprofile of the oxygen-containing gas and the nitric oxide-containing gasprogressively decreases throughout the remainder of inspiration.
 29. Amethod of delivering nitric oxide via delivery means to a mechanicallyor spontaneously breathing patient having a certain inspiration profilecomprising the steps of: supplying in a first breath a mixture ofoxygen-containing gas and a nitric oxide-containing gas to the deliverymeans, the oxygen-containing gas and a nitric oxide-containing gashaving a flow profile proportional or quasi proportional to theinspiration flow profile; supplying in at least one next breath, asource of enriched oxygen-containing gas having a flow profile that isproportional or quasi-proportional to the inspiration flow profile; andsupplying a source of air at or near the end of the first and nextbreaths to flush the delivery means of enriched oxygen and nitric oxide.30. A method of delivering a non-constant concentration of nitric oxideto a spontaneously breathing patient via delivery means comprising thesteps of: detecting the onset of inspiration; determining theinspiration flow profile for an individual breath; supplying anoxygen-containing gas to the delivery means, the oxygen-containing gashaving a flow profile that tracks the inspiration flow profile;supplying an nitric oxide-containing gas to the delivery means, thenitric oxide-containing gas having a flow profile that is less than, butclosely tracks the oxygen-containing gas flow profile at the beginningof inspiration, wherein the difference between the flow profile of theoxygen-containing gas and the flow profile of the nitricoxide-containing gas progressively increases through the remainder ofinspiration; and wherein the delivery means is an endotracheal tube. 31.A method of delivering a non-constant concentration of nitric oxide to aspontaneously breathing patient comprising the steps of: detecting theonset of inspiration; determining the inspiration flow profile for anindividual breath; supplying an oxygen-containing gas to the deliverymeans, the oxygen-containing gas having a flow profile that tracks theinspiration flow profile; supplying an nitric oxide-containing gas tothe delivery means, the nitric oxide-containing gas having a flowprofile that is substantially less than the oxygen-containing gas flowprofile at the beginning of inspiration compared to the end ofinspiration, and wherein the difference between the flow profile of theoxygen-containing gas and the flow profile of the nitricoxide-containing gas progressively decreases throughout the remainder ofinspiration; and wherein the delivery means is an endotracheal tube. 32.A method of delivering nitric oxide to a spontaneously breathing patientvia delivery means comprising the steps of: detecting the onset ofinspiration; supplying an oxygen-containing gas to the delivery means,the oxygen-containing gas having a pre-programmed flow profile; andsupplying an nitric oxide-containing gas to the delivery means, thenitric oxide-containing gas having a pre-programmed flow profile that isproportional or quasi-proportional to the flow profile of theoxygen-containing gas throughout inspiration.
 33. A device fordelivering nitric oxide to a spontaneous-breathing patient comprising: asource of an oxygen-containing gas connected via tubing to a patientinspiration interface device; a source of an nitric oxide-containing gasconnected via tubing to the patient inspiration interface device; afirst proportional flow controller located between the source ofoxygen-containing gas and the patient inspiration interface device forvarying the flow rate of the oxygen-containing gas to the patientinspiration interface device; a second proportional flow controllerlocated between the source of nitric oxide-containing gas and thepatient inspiration interface device for varying the flow rate of thenitric oxide-containing gas to the patient inspiration interface device;an inspiration flow profile sensor that detects the onset of inspirationof the patient; and a controller for controlling the first and secondproportional flow controllers in response to the detection of the onsetof inspiration from the inspiration flow profile sensor, the first andsecond proportional flow controllers being controlled such that thenitric oxide-containing gas has pre-programmed flow profile that isproportional or quasi-proportional to the flow profile of theoxygen-containing gas throughout inspiration.